The Discovery of Ivermectin

 

The Discovery of Ivermectin

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This story is so far-fetched it seems unbelievable: a sample of soil found in Japan ends suffering in Africa. It all begins when a scientist comes across a humble bacterium on a golf course outside Tokyo. Then a team of scientists in the US discover that this bacterium produces compounds that block the activity of nematodes, roundworms. They develop this compound into a drug that prevents the proliferation of parasites in countless pets and farm animals, avoiding millions in losses worldwide. Amazingly, this same drug also serves to prevent and treat human diseases caused by parasitic worms. Without this treatment, these diseases would cause blindness and many other serious symptoms in hundreds of millions of people living in the poorest countries.

 

The story involves thousands of scientists from around the world, as well as doctors, health workers and other very dedicated participants. Also involved are a major pharmaceutical company and a research institute, both willing to give away a drug to rid developing countries of debilitating diseases.

 

And none of this would have happened if no one had been nosy about analyzing soil samples in Japan.

In 1971, Ōmura decided to take a sabbatical and spend time in the laboratory of Max Tishler (1906-1989), an eminent professor of chemistry at Wesleyan University in Connecticut, USA. A year earlier, Tishler had retired after a successful career at the pharmaceutical company Merck. Before returning home in 1973, Ōmura managed to secure a pioneering agreement between Merck and its research center in Japan. In Kitasato they would continue to collect and analyze samples, but they would send the most promising ones to Merck's research laboratories in Rahway, New Jersey (USA). There they could do further tests and develop drugs, but the Japanese institute would retain the rights and royalties on any products that were eventually marketed.

At Merck's research labs, a team led by parasitology expert William C. Campbell (born 1930) began testing the samples as a possible treatment for parasitic worms. Campbell, who had studied veterinary medicine and zoology, identified several compounds that could be used as medicines for livestock and other animals.

 

To test these treatments, Merck researchers infected mice with nematode worms and then fed them the different cultures prepared by Ōmura's team. They found that one of the cultures was remarkably effective at killing parasites. Specifically, this sample came from a soil sample collected near a golf course in Kawana, about 80 miles (130 kilometers) southwest of Tokyo. Ōmura identified the bacteria in that culture as a new strain, which was eventually named Streptomyces avermectinius.

 

The Merck team isolated the active compound produced by the bacteria and called it "avermectin." They later discovered that avermectin is actually a mixture of eight very similar compounds. So they began modifying these substances using different chemical reactions, tweaking their molecular structures in very subtle ways to try to make avermectin more effective against parasites and, at the same time, safer for animals. Merck scientists discovered a small modification that achieved both of these effects and named the resulting pair of molecules "ivermectin." This mixture was 25 times more potent than the treatments of the time against parasitic worms.

 

Merck carried out further analyses that showed that ivermectin could also be used to combat mites, fleas and oestrids, all of which are parasites that cause huge economic losses in livestock. It worked well on horses, cows, pigs, sheep and dogs; ivermectin was safe and harmless for all of these animals.

 

These promising results led Merck to market ivermectin as a veterinary treatment in 1981. From 1987, this compound began to be sold to the public under the trademark Heartgard® to prevent the appearance of worms in dogs (today, the animal health company Merial markets this drug). Very soon, these products became the best-selling veterinary drugs, generating sales of more than one billion US dollars a year.

A treatment for river blindness

A child helps a man suffering from onchocerciasis (river blindness) in Sierra Leone.

Children and young people often accompany and guide people affected by onchocerciasis (river blindness). This disease is one of the major causes of preventable blindness. In 1987,

ivermectin was approved for use in humans to treat this disease 

 

The cycle of parasitic diseases often begins with an insect bite.

 

Black flies that breed near river rapids carry larvae of the worm that, in humans, causes onchocerciasis. A disease also known as "river blindness." When a fly infects a human, it can cause the disease to spread to the surrounding environment.

A treatment for river blindness

 

The cycle of parasitic diseases often begins with an insect bite.

 

Black flies that breed near river rapids carry larvae of the worm that causes onchocerciasis in humans. This disease is also known as "river blindness." When an infected fly bites a person, it deposits larvae of the worm on the skin and the parasite enters the body through the wound. There, they mature into adulthood and are able to reproduce. Female worms release thousands of microscopic larvae that can travel throughout our body. When they reach the eyes, they cause wounds and form scar tissue that causes blindness. In addition, the parasite also causes itching and disfigurement of the skin. This disease occurs mainly in Africa, but there are also cases in Yemen and several Latin American countries. It is one of the biggest causes of blindness in the world and is preventable.

 

Campbell encouraged his colleagues to study the potential of ivermectin to treat river blindness. It is an exciting drug because it has no antiviral or antibiotic activity and very few side effects. Researchers found that this is due to ivermectin's mechanism of action, which blocks cellular channels in the worms that are not accessible in pets, livestock, or humans. In young worms, the drug disrupts the function of these channels in muscle and nerve cells, causing paralysis. In addition, the drug makes the more immature worms more vulnerable to our immune system and prevents adult female worms from releasing larvae. All of these effects combined help to eliminate all parasites.

 

In its efforts to develop new medicines, Merck worked with the World Health Organization (WHO) to design and implement human clinical trials in 1981. Led by Mohammed Aziz (1929-1987), scientists evaluated the efficacy of ivermectin in treating river blindness in Senegal. The results with a single dose of the pill were highly effective in treating this disease and the drug was approved for human use in 1987 under the name Mectizan®.

William Campbell (right) speaks with Mohammed Aziz (center) and Kenneth Brown (left) at a 1987 press conference in Washington, D.C.,

With affection,

Ruben